Oral ingestion of water greatly elevates blood pressure in individuals with impaired autonomic reflexes. While[unreadable] the effect averages 30-40 mmHg, there is large interindividual variation with occasional increases of 100[unreadable] mmHg. We were initially startled by the magnitude of this response, but others have now replicated it and[unreadable] confirmed its magnitude. An effect is also found in treated hypertensive subjects and in normal subjects,[unreadable] albeit it at smaller magnitude. We have also found that ingestion of water potentiates the effect of the pressor[unreadable] drug phenylpropanolamine (PPA). In view of its magnitude and robustness, the pressor response to water[unreadable] may signal an important but heretofore unrecognized mechanism at work in human cardiovascular regulation[unreadable] both in health and disease. The water response may have important diagnostic and therapeutic implications.[unreadable] In particular, it may be the major unrecognized determinant of noise in blood pressure assessment in the[unreadable] older population, and might possibly be a source of interindividual and intraindividual variation in orthostatic[unreadable] tolerance.[unreadable] [unreadable] The purpose of this proposal is to address the mechanism of the cardiovascular effect of water ingestion,[unreadable] and address the basis of interindividual variation in this gastropressor response. We seek to understand if[unreadable] the sympathetic nervous system is mediating water's pressor response in Specific Aim 1. In Specific Aim 2,[unreadable] we try to determine the macroscopic stimulus underlying the response. In Specific Aims 3 and 4, we address[unreadable] potential efferent mechanisms at a more molecular level in both human subjects and in a mouse model[unreadable] system. Finally in Specific Aim 5 we try to determine the basis of the age dependency of the pressor[unreadable] response to water.[unreadable] [unreadable] Although water is a part of daily life, we believe the gastropressor response we have observed may have[unreadable] important consequences in health and disease.